Diarylaminopropanediol and diarylmethyl-oxazolidinone compounds

ABSTRACT

A method for preparing a diarylalanine compound is provided. The method includes reacting a diarylaminopropanediol with a reducing agent to form a diarylaminopropanol compound and/or contacting a serine ester derivative with an aryl metal reagent to form diarylaminopropanediol. A diarylmethyloxazolidinone compound is also provided.

This application is a continuation of Ser. No. 08/410,861 filed Mar. 10,1995 now U.S. Pat. No. 5,623,087.

BACKGROUND OF THE INVENTION

Bulky unnatural amino acids, such as diarylalanines, are of interestsince these compounds may serve as surrogates for their naturalcounterparts. Since the aromatic rings of phenylalanine and tyrosineamino acid residues often play important roles in peptide-receptorinteractions, replacement of one of these residues with a bulkydiarylalanine residue, e.g., diphenylalanine, has the potential todramatically enhance the therapeutic activity of peptide analogs.Incorporation of a diarylalanine into a bioactive peptide may alsoimpart biostability by inhibiting degradation by peptidases and/orprovide conformational restriction. Either effect can serve to increasethe pharmacological activity of a polypeptide and increase its potentialas a therapeutic agent. For example, a peptidyl antagonist whichincorporates an optically active form of a diarylalanine, theD-enantiomer of diphenylalanine (D-DIP), is known to be a potentantagonist of the endothelin ET_(A) and ET_(B) receptors. A number ofluteinizing hormone-releasing hormone analogs containing varioushydrophobic unnatural amino acid substitutions have been reported tohave potent biological activity. Hydrophobic peptides which include a3,3-diphenylalanine residue have been reported to have antihypertensiveactivity.

A series of angiotensin II analogs in which the phenylalanine at the8-position was replaced with various unnatural amino acids including3,3-diphenylalanine have also been described. The authors of this studyindicated that they were unable to resolve the 3,3-diphenylalanineenzymatically using either carboxypeptidase or hog kidney acylase. Inorder to obtain the desired angiotensin II analog it was necessary toseparate via countercurrent distribution the diastereomeric peptideswhich had been prepared from racemic 3,3-diphenylalanine. While thispermitted the desired analog to be obtained, the approach was extremelyinefficient since half of the product produced was the undesireddiastereomer.

In order for unnatural amino acids such as diphenylalanine to becomeeffective building blocks for the design of peptide analogs, methodswhich permit the unnatural amino acids to be readily prepared in highyield and in optically active form must be available.

A number of preparations of diphenylalanine (DIP) in racemic form havebeen reported. The unnatural amino acid has been prepared throughalkylation of an acetamidomalonate ester or a hindered imine of asubstituted glycinamide. A derivative of DIP has also been producedthrough an azide addition to a 3,3-diphenylpropionamide. Other routes,such as the alkylation and subsequent reduction of a nitroacetic acidester are also known. These routes have not provided access to theoptically active forms of DIP, nor have they facilitated the preparationof a wide variety of analogs with differing aryl groups.

Several unsuccessful attempts to resolve diphenylalanine by enzymaticresolution of a racemic derivative have been reported. These includeunsuccessful attempts to selectively hydrolyse N-BOC diphenylalanineusing papain or α-chymotrypsin. An effort to selectively hydrolyseN-acetyl DIP using hog kidney acylase or carboxypeptidase was alsoreported to be unsuccesful.

Both the D- and L-isomers of DIP have been obtained from the racemate byconventional resolution using cinchona alkaloids. This techniquehowever, which requires the repeated recrystallization of an alkaloidsalt, is not especially attractive for the preparation of largequantities of the unnatural amino acid.

More recently, there have been several reports of the preparation of DIPvia asymmetric synthesis. These reports include asymmetric alkylation ofa sultam-derived glycine imine, stereoselective alkylation of a hinderedglycine imine in the presence of a cinchona-based phase transfercatalyst, and asymmetric azide addition to a 3,3-diphenylpropionamideusing chiral auxiliary methodology. The chiral auxiliary based methodsrequire extra steps for the introduction and cleavage of the chiralauxiliary, which is typically incorporated into a precursor as part ofan amide derivative. As with the chiral phase transfer method, thechiral auxiliary methods include a purification step to remove the agentwhich confers chirality.

All of the methods described above suffer from one or more of a numberof disadvantages low yields, general difficulty in scaling up theprocedure, use of costly reagents, inclusion of extra reaction orpurification steps to introduce and/or remove a chiral agent, and theinability to alter the preparation to provide a variety of relatedderivatives. Accordingly, in view of the potential utility ofdiarylalanines in the preparation of peptide analogs and other compoundsof pharmaceutical interest, there is a continuing need for methods whichwould permit the efficient, large scale preparation of a variety ofdiarylalanines and if desired, in optically active form.

SUMMARY OF THE INVENTION

The present invention provides a method for preparing a diarylalaninecompound, such as diphenylalanine. The method provides a short and highyielding synthesis of the diarylalanine from readily available serinealkyl esters. The method uses commonly available reagents and isamenable to large scale synthesis. Moreover, the present method permitsthe chiral synthesis of diarylalanines in excellent optical purity fromchiral serine alkyl esters. For example, using the present method,(R)-diphenylalanine (D-diphenylalanine) may be efficiently prepared inexcellent optical purity starting from the hydrochloride salt of(S)-serine methyl ester (L-serine methyl ester). The present method alsoallows the synthesis of a wide variety of other unnatural aromatic aminoacids by simply varying the aryl metal reagent which is used in one ofthe steps.

One embodiment of the method includes reacting a diarylaminopropanediolwith a reducing agent to form a diarylaminopropanol compound. Anotherembodiment of the method includes contacting a protected serine estercompound with an aryl metal reagent to form a protecteddiarylaminopropanediol compound. A third embodiment of the presentmethod includes contacting a serine ester hydrochloride compound with anaryl metal reagent to form a diarylaminopropanediol compound.

The present invention is also directed to a protecteddiarylaminopropanediol compound represented by the formula: ##STR1##

In addition, the present invention provides a diarylmethyloxazolidinonecompound represented by the formula: ##STR2##

The present invention also provides a method for preparing adiarylmethyloxazolidinone compound which includes reacting adiarylhydroxymethyloxazolidinone compound with a reducing agent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method which includes the step ofreacting a diarylaminopropanediol compound represented by the formula:##STR3## with a reducing agent to form a diarylaminopropanol compoundrepresented by the formula: ##STR4## The step may be used for thepreparation of the diarylaminopropanol compound or may be employed as astep in a process of producing a diarylalanine. For the purposes of thisinvention, the term "diarylalanine" includes the free form of the aminoacid as well as salts and N-protected derivatives thereof. The Ar is asubstituted or unsubstituted aromatic group, e.g., phenyl or naphthyl.P¹ and P² are hydrogen or any of a wide variety of standard protectinggroups known to be used for the protection of alcohols or amine may beemployed. Typically, P¹ and P² are independently hydrogen, --C(O)R¹, or--C(O)OR², where R¹ and R² are each an alkyl, cycloalkyl, phenyl,arylalkyl, fluorenyl or allyl group. The R¹ and R² groups may besubstituted with one or more substituents such as a halogen atom, analkyl group or an alkoxy group. P¹ and P² may also both be part of asingle protecting group which forms a ring (e.g., where P¹ and P²together are ##STR5## Typically, P¹ and/or P² are chosen to beprotecting groups which are not cleaved and are substantially unreactiveunder the conditions of the particular step to which the protected amineand/or alcohol is to be subjected. The protecting groups may be removedand/or switched to improve the compatibility of a protected derivativewith particular reaction conditions. Preferably, the same protectinggroup is employed throughout as much of the reaction sequence aspossible. This obviates the need to include additional steps directedsolely to the removal or introduction of a protecting group and enhancesthe overall efficiency of the sequence.

Examples of suitable alcohol protecting groups, P¹, include --C(O)R¹,where R¹ is a substituted or unsubstituted C₁ -C₁₀ alkyl group, asubstituted or unsubstituted C₁ -C₇ cycloalkyl group, a substituted orunsubstituted arylalkyl group, or a substituted or unsubstituted phenylgroup. Among preferred P¹ groups are acetyl (CH₃ C(O)--) and propionyl.Depending on the reaction conditions, the alcohol group may be leftunprotected, i.e., P¹ is hydrogen.

P² is typically hydrogen, an amide group (--C(O)R²), or a carbamategroup (--C(O)OR³). If P² is an amide group, R² may be hydrogen, asubstituted or unsubstituted C₁ -C₁₀ alkyl group, a substituted orunsubstituted C₃ -C₇ cycloalkyl group, a substituted or unsubstitutedarylalkyl group, or a substituted or unsubstituted phenyl group. If P²is an amide group, R³ may be a substituted or unsubstituted C₁ -C₁₀alkyl group, a substituted or unsubstituted C₃ -C₇ cycloalkyl group, asubstituted or unsubstituted arylalkyl group (e.g., benzyl), asubstituted or unsubstituted phenyl group, a substituted orunsubstituted fluorenyl group, a substituted or unsubstituted allylgroup. Examples of preferred P² groups include acetyl, propionyl,carbobenzyloxy (CBZ), tertiary butoxycarbonyl (BOC),fluorenylmethoxycarbonyl (FMOC), ethoxycarbonyl and methoxycarbonyl.

In addition, P¹ and P² may be joined together to form a ring with theamino alcohol. For example, P¹ and P² together may be ##STR6## so thatthe amino and alcohol groups are protected as part of an oxazolidinonering.

The protecting groups P¹ and P² are typically unsubstituted. However, insome instances substituted protecting groups of the types listed abovemay be employed in order to modify the reactivity of a particularprotecting group. A large number of substituted and unsubstitutedprotecting groups for alcohols and/or amines together with methods fortheir preparation and removal are described in Protective Groups inOrganic Synthesis, Greene, ed., John Wiley & Sons, New York (1981) andProtecting Groups, Kocienski, Thieme, Stuttgart (1994), the disclosureof which are incorporated by reference.

The present method may be employed to prepare a wide variety ofdiarylalanine compounds. For the purposes of this invention, the term"diarylalanine compound" include the parent amino acid as well as saltsthereof and N-protected derivatives (e.g., N-BOC-diarylalanine,N-FMOC-diarylalanine and N-acetyldiarylalanine). Suitable aryl groupsinclude any aromatic group for which a corresponding aryl Grignardreagent or aryl lithium reagent may be prepared. Examples of suitablearyl groups include aromatic hydrocarbons such as a phenyl group or anaphthyl group, as well as aromatic heterocyclic groups such as apyridine group or a furan group. The aromatic group may optionally besubstituted with one or more substituents so long as the substituentsare substantially inert to the reaction conditions of the presentmethod. Typical substituents include fluorine, chlorine, alkyl groupshaving from 1 to 10 carbon atoms (e.g., methyl or ethyl), alkoxy groupshaving from 1 to 10 carbon atoms (e.g., methoxy or ethoxy), alkoxyalkylgroups having from 1 to 10 carbon atoms and one or more oxygen atoms, oramido groups having from 1 to 10 carbon atoms, such as acetamido. Thesubstituent(s) may also be a fluorinated alkyl group having from 1 to 10carbon atoms (e.g., trifluoromethyl) or a fluorinated alkoxy groupshaving from 1 to 10 carbon atoms (e.g., trifluoromethoxy). Preferablythe aromatic groups are a phenyl group or a naphthyl group which areeither unsubstituted or are substituted with fluorine, a lower alkylgroup (having from 1 to 6 carbon atoms), a lower alkoxy group (havingfrom 1 to 6 carbon atoms), or trifluoromethyl. ##STR7##

Scheme 1 depicts one embodiment of the present method for preparing adiarylalanine compound. The synthetic route shown in Scheme 1 allows thepreparation of a diphenylalanine in six steps from the hydrochloridesalt of a serine ester. The embodiment includes the reaction ofdiarylaminopropanediol compound C with a reducing agent to formdiarylaminopropanol compound D. The method may also include the reactionof an aryl metal reagent, such as a phenyl magnesium halide or an aryllithium reagent, with the serine ester hydrochloride. The serine estertypically includes an alkyl group having from 1 to 10 carbon atoms orarylalkyl group having from 5 to 12 carbon atoms. Preferably, the estergroup is methyl, ethyl or benzyl.

In the sequence shown in Scheme 1, the reaction of the serine esterhydrochloride A with an aryl metal reagent producesdiarylaminopropanediol B. As discussed above the aryl metal reagent maybe a Grignard reagent (e.g., PhMgBr and or a substituted analog) or anaryl lithium reagent such as phenyl lithium or naphthyl lithium. Thearyl metal addition is typically run in an ether solvent such as diethylether, dimethoxyethane or tetrahydrofuran.

Diarylaminopropanediol B may then be reacted with a derivatizing agentto form protected diarylaminopropanediol C. The particular protectinggroup and the conditions used to prepare the protecteddiarylaminopropanediol C may be chosen from a wide variety of standardprotecting groups and techniques for preparing the protecteddiarylaminopropanediol.

Protected diarylaminopropanediol C may then be reacted with a reducingagent to form diarylaminopropanol D. A variety of reducing agents may beused to carry out the deoxygenation reaction. For example, thedeoxygenation may be achieved using a dissolving metal reducing agent,such as an alkali metal or alkaline earth metal. Preferably thedissolving metal reagent is an alkali metal such as sodium or lithiumand the reaction is run in the presence of liquid ammonia. When sodiumis used as the reducing agent, tetrahydrofuran may also be employed as acosolvent. Suitable conditions for the deoxygenation reaction alsoinclude the use of a hydrogen source (e.g., hydrogen (H₂), ammoniumformate or sodium borohydride) in the presence of a noble metal catalystsuch as palladium, platinum or rhodium. The noble metal catalyst istypically employed on a support such as carbon. In a preferredembodiment, the deoxygenation is run utilizing hydrogen or ammoniumformate as the hydrogen source in the presence of a palladium catalyst(e.g., palladium on a carbon support).

The deoxygenation reaction may also be carried out using any of a numberof other common reducing agents. Included among suitable common reducingagents which may be employed are sodium borohydride (in the presence oftrifluoroacetic acid), triethylsilane (in the presence oftrifluoroacetic acid), red phosphorus (in the presence of iodine andacetic acid), lithium borohydride (in the presence of aluminum chloride)and metallic tin (in the presence of hydrochloric acid and acetic acid).The deoxygenation may also be run with raney nickel as the reducingagent in the presence of a suitable solvent such as an alcohol or anether.

The preparation of the diarylalanine is completed through the oxidationof N-protected diarylaminopropanol D' with an oxidizing agent. In orderfor the oxidation step to be carried, P¹ must be hydrogen and P² must bea protecting group which is stable under the oxidation conditions.Diarylaminopropanol D may already include an appropriate N-protectinggroup. Alternatively, a different protecting group may be need to beintroduced or substituted onto the nitrogen atom. Where P¹ is nothydrogen, the selective removal of the O-protecting group may be carriedout to form N-protected diarylaminopropanol D'.

The N-protected alcohol D' may be oxidized under standard oxidationconditions to produce N-protected diarylalanine E. Finally, if desired,the N-protecting group may be removed by treating N-protecteddiarylalanine E with a deprotecting agent to obtain diarylalanine F.

A variety of conditions are suitable for carrying out the oxidationstep. Typically, the oxidation step is carried out using achromium-based oxidizing agent such as Jones reagent (CrO₃ /H₂ SO₄) .Oxygen (O₂) in the presence of a platinum catalyst (e.g., PtO₂) may alsobe used to effect the transformation of diarylaminopropanol D' todiarylalanine E.

One of the major advantages of the synthetic route shown in Scheme 1 isthat it can be carried out with substantially no racemization at theamino-bearing chiral center. This permits either (R)- or(S)-diarylalanine to be produced by selecting (S)-serine or (R)-serineas the respective starting material. The synthetic sequence depicted inScheme 1 shows the preparation of (R)-diphenylalanine starting from anester of (S)-serine. Diarylalanine of greater than about 70% andpreferably greater than about 95% optical purity can be prepared by thepresent method, i.e., the overall retention of optical activity over theentire sequence is typically at least about 70%. ##STR8##

Oxazolidinone G is readily available, for example from the reaction of aserine ester with phosgene or a dialkyl carbonate. As with the startingester in Scheme 1, the ester group "R" is typically an alkyl grouphaving from 1 to 10 carbon atoms or arylalkyl group having from 5 to 12carbon atoms. Preferably, the ester group is methyl, ethyl or benzyl. Aswith the synthetic route shown in Scheme 1, oxazolidinone G may be ineither racemic or optically active form. The use of an optically activeoxazolidinone (derived from either (R)- or (S)-serine) results in theproduction of an N-protected diarylaminopropanol D' having an opticalpurity comparable to the starting oxazolidinone.

Oxazolidinone G may be reacted with an aryl metal reagent to formdiarylhydroxymethyl oxazolidinone C". In this second step, the presenceof the acidic hydrogen atom on the nitrogen of the oxazolidinone ring isthought to protect the adjacent chiral center from racemization.Oxazolidinone C" represents an embodiment of the protecteddiarylaminopropanediol C (see Scheme 1) in which the carbonyl group actsas a protecting group for both the alcohol and the amine. As with thecorresponding reaction in Scheme 1, the aryl metal reagent may be anaryl magnesium halide (Grignard reagent, where the halide is notfluorine) or an aryl lithium reagent. Preferably the aryl metal reagentincludes a phenyl magnesium halide, where the phenyl group may besubstituted with one or more substituents selected from among methyl,ethyl, methoxy, ethoxy, fluorine, chlorine, trifluoromethoxy andtrifluoromethyl. The aryl magnesium halide is preferably a substitutedor unsubstituted aryl magnesium bromide.

The deoxygenation step which converts oxazolidinone C" intooxazolidinone D" may be carried out under the conditions described abovefor the transformation of diarylaminopropanediol C todiarylaminopropanol compound D. The same types of reducing agents andconditions may be used. Preferably, the deoxygenation is carried out bytreating diarylaminopropanediol C with a dissolving metal reagent in thepresence of liquid ammonia. More preferably, the dissolving metalreagent includes an alkali metal such as sodium or lithium. Thedeoxygenation may also be carried out by reacting oxazolidinone C" witha hydrogen source in the presence of a noble metal catalyst. If thisapproach is utilized, the deoxygenation is typically carried out byreacting oxazolidinone C" with hydrogen or ammonium formate in thepresence of a palladium, platinum or rhodium catalyst. The noble metalcatalyst preferably includes palladium. Most preferably, thedeoxygenation is carried out by treating the diarylaminopropanediol withsodium or lithium in the presence of liquid ammonia.

Oxazolidinone C" may be converted into the N-protecteddiarylaminopropanol D' through a two step process. Oxazolidinone C" maybe reacted with a protecting agent (e.g., BOC-anhydride) in the presenceof a base, such as a trialkylamine, sodium carbonate or potassiumcarbonate, to form the N-protected oxazolidinone H. Oxazolidinone H maythen be selectively ring opened to N-protected diarylaminopropanol D' bytreatment with cesium carbonate in an alcohol solvent such as methanol.

Oxazolidinone D", which is produced as an intermediate in the course ofthe approach shown in Scheme 2, may be used as a chiral auxiliary tofacilitate the preparation of optically active products from racemic orachiral starting materials. This type of technique is well known andrelated substituted oxazolidinones have been utilized to preparecarboxylic acid derivatives which can be stereoselectively alkylated(see e.g., Evans et al., JACS, 104, 1737 (1990); Evans et al., JACS,112, 4011 (1989); and Beylin et al., Tett. Letters, 953 (1993)).

Scheme 3 depicts another embodiment of the invention which allows thepreparation N-protected diarylaminopropanol D' starting from N-protectedserine ester I. As with the ##STR9## other serine esters describedabove, the ester "R" group is typically an alkyl group having from 1 to10 carbon atoms or arylalkyl group having from 5 to 12 carbon atoms and,preferably, is methyl, ethyl or benzyl. The N-protected serine ester ischosen such that the P² protecting group may be cleaved under reducingconditions (e.g., P² is a CBZ or FMOC group). The N-protected serineesters I may be readily prepared from the corresponding serine esterhydrochloride by using standard protecting group chemistry (e.g.,reaction with fluorenylmethoxycarbonyl-N-hydroxysuccinimide (FMOC-ONSu)or carbobenzyloxy chloride (CBZ-Cl)). As with the synthetic approachesshown in Schemes 1 and 2, the approach depicted in Scheme 3 may becarried out using racemic or optically active starting material.

Treatment of N-protected serine ester I with an aryl metal reagentproduces N-protected diarylaminopropanediol J. Reaction ofdiarylaminopropanediol J with a reducing agent results in bothdeoxygenation of the benzylic alcohol and removal of the protectinggroup P². Preferably the protecting group P² on aminopropanediol J is acarbobenzyloxy group (CBZ) and the reducing agent is a dissolving metalsuch as sodium or lithium. The dissolving metal reduction may be carriedout in a solvent which includes liquid ammonia and a cosolvent such astetrahydrofuran. If a hydrogen source is employed as the reducing agent,the reaction is preferably carried out in the presence of a palladiumcatalyst (e.g., 10% Pd/C).

The resulting diarylaminopropanol K may be converted into N-protecteddiarylaminopropanol D' using standard methods for the introduction ofprotecting groups. For example, the aminoalcohol may be treated withFMOC-ONSu to form N-FMOC diarylaminopropanol D'.

The invention will be further characterized by the following examples.These examples are not meant to limit the scope of the invention whichhas been fully set forth in the foregoing description. Variation withinthe concepts of the invention as described herein will be apparent tothose skilled in the art.

Scheme 4 shows a six step sequence used for the synthesis of(R)-diphenylalanine and three analogs starting from the ester of anaturally occurring amino acid, (S)-serine, or the correspondinganalogs. Examples 1-6 contain descriptions of the individual reactions.The synthesis of the diphenylalanines via this route is simple, requiresno chromatographic purification, and may be run on a large scale.##STR10##

EXAMPLE 1 Grignard Reactions with Serine Methyl Ester Hydrochloride

Grignard reagent was either purchased from a commercial source (AldrichChemical Company, Milwaukee, Wis.) or prepared in situ from thecorresponding aryl bromide. For in situ preparation, the bromide (193.54mmol) was added to magnesium turnings (193.54 mmol) over 45 min indiethyl ether at room temperature at such a rate that the ether mildlyrefluxed. After complete addition, the reaction was stirred at roomtemperature (2-2.5 h) until the magnesium was consumed. The resultingreagent was then transferred to an addition funnel and added dropwise to(S)-serine methyl ester hydrochloride (32.25 mmol) in diethyl ether atroom temperature. The reaction was stirred at room temperature for 12 to24 h and was quenched with 3M aqueous HCl (˜250 ml) or until pH was 2.The aqueous phase was separated and washed with methylene chloride (CH₂Cl₂ ; 3×100 ml) and the organic washes were discarded. The aqueous phasewas adjusted to pH 11-12 and then extracted with methylene chloride. Thecombined organic extracts were washed with water, brine, and dried overMgSO₄ and the solvent removed under vacuum to afford the respective(S)-diarylaminopropanediols, which did not require further purification.

Yields:

R═H--57%

R═CH₃ --42%

R═F--64%

R═OCH₃ --26%

EXAMPLE 2 Diacetylation with Acetic Anhydride

To a pre-cooled solution of (S)-diarylaminopropanediol (8.60 mmol;prepared according to Example 1) in pyridine (30.10 mmol) and CH₂ Cl₂(20 ml) was added acetic anhydride (25.80 mmol) dropwise over 10minutes. The reaction mixture was then stirred for 2 h. The reactionprogress was monitored by thin layer chromatography (TLC). Uponcompletion, the reaction mixture was diluted with CH₂ Cl₂ and washedwith 3M aqueous HCl (100 ml). The two phases were separated and theaqueous phase was re-extracted with CH₂ Cl₂ (2×50 ml). The combinedorganic extracts were washed with water, brine, and dried over MgSO₄.Concentration under vacuum furnished the respective (S)-diacetate inquantitative yield. The diacetates were further purified byrecrystallization using ethyl acetate and hexane. The yields for thediacetates obtained after recrystallization are shown below.

Yields:

R═H--73%

R═CH₃ --81%

R═F--87%

R═OCH₃ --74%

EXAMPLE 3 Deoxygenation

To an (S)-diacetate prepared according to Example 2 (2.75 mmol) in CH₃COOH (10 ml) was added ammonium formate (13.77 mmol) followed by Pd-C(10% Pd) (15% of the weight of the diacetate). The reaction mixture wasthen lowered into an oil bath pre-heated to 120° C. The reaction wasstirred at reflux for 2 to 6 h and monitored by TLC. Upon completion,the mixture was cooled and diluted with CH₂ Cl₂, and filtered over asmall bed of celite. The filtrate was washed with water, aqueous sodiumbicarbonate (NaHCO₃) solution, and brine. The organic layer was driedover anhydrous magnesium sulfate (MgSO₄) and concentrated under vacuumaffording a solid diacetylated (R)-diarylaminopropanol which was used inthe next reaction without further purification.

Yields:

R═H--74%

R═CH₃ --100%

R═F--90%

R═OCH₃ --100%

EXAMPLE 4 Mono-deacetylation using Guanidine

To a diacetylated (R)-diarylaminopropanol (5.6 mmol) prepared accordingto Example 3 in CH₂ Cl₂ (5 ml) was added 1M solution of guanidine (11.2mmol, 11.2 ml) in EtOH. The reaction progress was monitored by TLC. Uponcompletion, solvent was evaporated and the residue was dissolved in CH₂Cl₂ (50 ml). The resulting organic layer was washed with water andbrine. The organic layer was dried over anhydrous MgSO₄ and solvent wasevaporated yielding the respective N-acetyl (R)-diaryl-aminopropanol asa white solid. The N-acetyl diarylaminopropanols were used withoutfurther purification.

Yields:

R═H--82%

R═CH₃ --100%

R═F--93%

R═OCH₃ 86%

EXAMPLE 5 Oxidation of N-Acetyl Diarylaminopropanols with ChromiumTrioxide

To an N-acetyl (R)-diarylaminopropanol (2.02 mmol; prepared according toExample 4) in acetone (10 ml) was added Jones reagent (preparedaccording to Organic Synthesis, Vol. 5, p. 310) dropwise at roomtemperature until the reaction turned red. The reaction was monitored byTLC. After completion, isopropanol was added to quench the excess Jonesreagent or until the reaction color turned green. The solvent wasdecanted to separate the chromium salts. The residue was washed withacetone (2×20 ml) and again decanted. The combined supernatants wereconcentrated under vacuum and the residue dissolved in CH₂ Cl₂ (50 ml).The organic layer was washed with water to remove any chromiumimpurities. Further purification via acid/base extraction furnished thedesired N-acetyl (R)-diarylalanine as a white solid.

Yields:

R═H--88%

R═CH₃ --97%

R═F--91%

R═OCH₃ --27%

EXAMPLE 6 Deacetylation with Hydrochloric Acid

An N-acetyl (R)-diarylalanine prepared according to Example 5 (1.0 mmol)in 6 M aqueous HCl was heated to reflux for 3 to 9 hr or until thestarting material had completely dissolved. The reaction mixture wasthen cooled and water was removed under vacuum to afford thehydrochloride salt of the respective (R)-diarylalanine in high yield.The amine hydrochlorides were further purified by recrystallization.

Yields:

R═H--96%

R═CH₃ --100%

R═F--100%

R═OCH₃ --70%

Scheme 5 shows an alternative sequence employed for the preparation ofN-BOC-(R)-diphenylalanine starting from (S)-serine methyl ester(L-serine methyl ester). Examples 7 and 10-14 contain descriptions ofthe individual reactions depicted in Scheme 5. Examples 8 and 9 reportthe preparation of (S)-4-(hydroxydiphenylmethyl)-2-oxazolidinone from(S)-3-hydroxydiphenylalaninol (the preparation of which is described inExample 1) via an alternative approach. ##STR11##

EXAMPLE 7 (S)-4-Carbomethoxy-2-oxazolidinone

To (S)-serine methyl ester hydrochloride (20 g, 128.64 mmol) in water(230 ml) was added KHCO₃ (14.16 g, 141.52 mmol) and K₂ CO₃ (19.56 g,141.52 mmol) at room temperature. It was then cooled by an ice bath andtriphosgene (19.04 gm, 64.32 mmol) was added in toluene (192 ml) via anaddition funnel over 25 minutes. The reaction mixture turned cloudy.After 2 h, reaction phases were separated and the aqueous layer waslyophilized to yield (S)-4-carbomethoxy-2-oxazolidinone as a white solid(16.5 g) in 88% yield.

EXAMPLE 8 (S)-4-(Hydroxymethyldiphenyl)-2-oxazolidinone

Phenyl magnesium bromide was prepared by slow addition of bromobenzene(14.53 ml, 137.93 ml) in THF (50 ml) to Mg (3.31 g, 137.93 g atom). Thereaction mixture was stirred for one hour or until most of the Mg hadbeen consumed. (S)-Carbomethoxy oxazolidinone (5 g, 34.48 mmol; preparedaccording to Example 7), dissolved in THF (25 ml), was added dropwiseover 15 min period and allowed to stir an additional hour. The reactionmixture was then cooled with an ice bath and aqueous 2 M HCl (85 ml) wasadded dropwise which resulted in the formation of crystals. The reactionmixture was transferred to a 500 ml round bottom flask aided with 100 mlEtOAc and the organics were evaporated. Aqueous Na₂ SO₃ (30 ml) wasadded along with 100 ml hexane. The mixture was shaken and the whitecrystals were filtered. Crystals were washed with hexane (50 ml) toremove-biproduct and dried to furnish the desired(S)-hydroxymethyldiphenyloxazolidinone (6.79 g) in 73% yield. mp:227-230° C., α! _(D) ²⁵ =-14.85, (C=1.3, DMSO).

EXAMPLE 9 (S)-4-(Hydroxydiphenylmethyl)-2-oxazolidinone

To (S)-3-hydroxydiphenylalaninol (40 g, 164.61 mmol; prepared accordingto Example 1), anhydrous K₂ CO₃ (2.3 g, 16.46 mmol) was added diethylcarbonate (50 ml, 411.52 mmol). The reaction mixture was lowered into anoil bath preheated to 135° C., and was stirred until 46 ml EtOH wascollected as the distillate. The oil bath was removed upon cessation ofEtOH distillation and the reaction mixture was cooled and CH₂ Cl₂ (750ml) was added. The reaction mixture was transferred to a separatoryfunnel, and the organics were washed with water (750 ml). The organicphase was dried over MgSO₄ and concentrated on a rotavap to furnish thedesired (S)-hydroxydiphenylmethyloxazolidinone (43 g) in 93% yield.

EXAMPLE 10 (S)-4-(Hydroxydiphenylmethyl)-2-oxazolidinone

To a mixture of (S)-3-hydroxydiphenylalaninol (2.43 g, 10.00 mmol;prepared according to Example 1), Et₃ N (8.34 ml, 60.00 mmol) in CH₂ Cl₂(30 ml) was added triphosgene (0.98 g, 3.3 mmol) in CH₂ Cl₂ (5 ml) at 0°C. The reaction mixture was stirred for 30 min. and diluted with CH₂ Cl₂(50 ml). The organic phase was washed with water (50 ml) and dried overMgSO₄ and subsequent concentration in vacuum afforded the desired(S)-hydroxydiphenylmethyloxazolidinone (2.6 g) in 92% yield.

EXAMPLE 11 (R)-4-(Methyldiphenyl)-2-oxazolidinone

To the (S)-hydroxydiphenylmethyloxazolidinone (5 g, 18.59 mmol; preparedaccording to Example 8, 9 or 10) in freshly distilled ammonia (250 ml)was added Na metal (1.28 g, 55.77 g atom) in intervals. The reactionmixture was stirred for 2 h at -330° C. Ammonia was evaporated and MeOH(20 ml) was added to the white residue. The residue was treated with 1 Maqueous HCl (˜100 ml). The organics were extracted with CH₂ Cl₂ (3×50ml). The combined organic extracts were washed with water and brinesuccessively. Drying over anhydrous MgSO₄ and concentration in vacuumafforded a yellowish mass, which upon crystallization in EtOH gave thedesired (R)-methyldiphenyloxazolidinone (3.32 g) in 70% yield. mp:128-130° C., α!_(D) ²⁵ =+25.70, (C=2.0, CH₂ Cl₂).

EXAMPLE 12(R)-N-(tert-Butyloxycarbonyl)-4-(methyldiphenyl)-2-oxazolidinone

To a premixed solution of (R)-methyldiphenyloxazolidinone (1.00 g, 3.95mmol; prepared according to Example 11), BOC-anhydride (1.03 g, 4.74mmol) and dimethylaminopyridine (DMAP; catalytic) in CH₂ Cl₂ (10 ml) wasadded Et₃ N (0.715 ml, 5.14 mmol) at room temperature. The reactionmixture was worked up after 30 min. by addition of water (50 ml) andextraction of the aqueous layer with CH₂ Cl₂ (3×20 ml). The combinedorganic extracts were washed with water and brine. Drying over MgSO₄followed by concentration in vacuum afforded a white solid, which wasthen dissolved in EtOAc. Addition of hexane to the organic solutionprecipitated the desired (R)-methyldiphenyloxazolidinone as a whitesolid (1.12 g) in 80% yield. mp: 103-105° C., α!_(D) ²⁵ -30.90 (C=1.0,CH₂ Cl₂)

EXAMPLE 13 (R)-2-N-(tert-Butyloxycarbonyl)-3,3-diphenyl-1-propanol

Cesium carbonate (0.178 g, 0.55 mmol) was added to the methanolicsolution (40 ml) of N-BOC (R)-methyldiphenyl oxazolidinone (1.964 g,2.73 mmol; prepared according to Example 12). The reaction mixture wasstirred for 2.5 h at room temperature and then quenched with solidcitric acid (90.155 g, 0.55 mmol). Methanol was evaporated in vacuum.The crude solid was then dissolved in CH₂ Cl₂ (30 ml) and the organiclayer was washed with water and brine and dried over MgSO₄.Concentration on a rotavap afforded N-BOC (R)-diphenylalaninol as awhite solid in 90% yield which needed no purification, but waschromatographed for analytical purposes (0.611 g, 88% yield). mp:150-152° C., α!_(D) ²⁵ =-36.2 (C=1.0, MeOH).

EXAMPLE 14 (R)-N-(tert-butyloxycarbonyl)-diphenylalanine

Jones reagent (chromium trioxide in sulfuric acid and water) was addedto N-BOC-(R)-diphenylalaninol (0.255 g, 1.0 mmol; prepared according toExample 13) in acetone (10 ml) until the reaction mixture retained a redcolor. The reaction mixture was then quenched with addition ofisopropanol. The precipitated chromium salts were filtered through a padof celite. The filtrate was concentrated on a rotavap. The resultant wasdissolved in EtOAc (20 ml) and the organic layer was washed with water.Acid base extraction yielded N-BOC-(R)-diphenylalanine as a white powder(0.217 gm) in 80% yield. mp: 150-152° C.; lit. 153-154° C., α!_(D) ²⁵=-36.2 (C=1.0, MeOH); lit. α!_(D) ²⁵ -35.7 (C=1.0, MeOH).

Scheme 6 shows an alternative five step sequence employed for thepreparation of N-FMOC-(R)-diphenylalanine starting from L-serine methylester hydrochloride. Examples 15-19 contain descriptions of theindividual reactions depicted in Scheme 6. ##STR12##

EXAMPLE 15 (S)-N-(Benzyloxycarbonyl)-serine Methyl Ester

To (S)-serine methyl ester hydrochloride (70 g, 0.45 mol) in water (850ml) was added NaHCO₃ (125.2 g, 1.49 mol) slowly. The mixture was stirredat room temperature for 15 min. and benzyloxycarbonyl chloride (77 ml,0.54 mol) was added via an addition funnel. The reaction was stirred foran additional 12 h. The reaction mixture was extracted with CH₂ Cl₂(3×300 ml). The organic layer was dried over MgSO₄ and concentrated invacuum to give N-Z-(S)-serine methyl ester as an oil (113.9 g) in yield,which solidified upon cooling in the refrigerator. α!_(D) ²⁵ =-13.780°(C=1.32, MeOH).

EXAMPLE 16 (S)-2-N-(Benzyloxycarbonyl)-2,2-diphenyl-1,3-propanediol

Phenyl magnesium bromide was prepared by addition of bromobenzene (209ml, 1.98 mol) in Et₂ O (300 ml) at 0° C. to Mg metal (48 g, 1.98 g atom)in Et₂ O (500 ml). To this red solution was added N-Z-(S)-serine methylester 800 in ether (114 g, 0.45 mol) via an addition funnel at 0° C. Thereaction was stirred for an additional 12 hr and quenched with 250 ml ofconc. HCl in ice (˜1 kg). The entire mass was extracted with EtOAc(3×100 ml). The combined organic phase was washed with water followed bybrine. Drying over MgSO₄ and concentration in vacuum afforded thedesired N-Z-(S)-diphenylaminopropanediol as a solid. The solid wasfurther purified by recrystallization using EtOAc and hexane to yield(127.94 g; 75%) of the desired product.

EXAMPLE 17 (R)-Diphenylalaninol

To N-Z-(S)-diphenylaminopropanediol (24 g, 98.76 mmol) in freshlydistilled NH₃ (700 ml) was added Na metal (6.814 g, 296.3 g atom) inintervals over 2.5 h. The reaction mixture was then quenched with solidNH₄ Cl (21 g) and NH₃ was allowed to evaporate and quenched with 1 MHCl. The resulting white residue was extracted with CH₂ Cl₂ (3×100 ml)and the combined organic phase was washed with water followed by brine.Drying over MgSO₄ and concentration in vacuum afforded(R)-diphenylalaninol as a solid (21 g) in quantitative yield. Furthercrystallization using EtOAc afforded a white powder (17 g) in 82% yield.mp: 108-111° C., α!_(D) ²⁵ =-42.66 (C=1.35, CH₂ Cl₂)

EXAMPLE 18 (R)-N-(9-Fluorenylmethoxycarbonyl)-diphenylalaninol

To (R)-diphenylalaninol (8.3 g, 36.56 mmol) in aqueous THF (1:9, v/v,180 ml) was added 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide(FMOC-ONSu; 11.09 g, 32.90 mmol) and the reaction mixture was stirred atroom temperature for 12 h. The reaction mixture was extracted with EtOAc(3×50 ml) and the two phases were separated. The combined organic phaseswere washed successively with 1 M aqueous HCl (50 ml), water, then withbrine, and dried over MgSO₄. Concentration in vacuum affordedN-FMOC-(R)-diphenylalaninol as a pale yellow solid (14.3 g) in 96% yield(based on the quantity of FMOC-ONSu used) which was used without furtherpurification. The unreacted (R)-diphenylalaninol was recovered byacidification of the aqueous layer (0.8 g).

EXAMPLE 19 (R)-N-(9-Fluorenylmethoxycarbonyl)-diphenylalanine

The Jones reagent (CrO₃ in H₂ SO₄ and water) was added dropwise at roomtemperature to a solution of N-FMOC-(R)-diphenylalaninol (14.4 g, 31.84mmol) in acetone (140 ml) until the solution attained red color. Thereaction mixture was quenched with addition of isopropanol. Theprecipitated chromium salts were filtered through a pad of celite andfiltrate was concentrated in vacuum. To this green residue was added CH₂Cl₂ (300 ml) and the organic layer was washed with water to removechromium impurities. The two phases were separated and organic phase wasconcentrated in vacuum. The residue was treated with dilute aqueous NH₄OH solution (150 ml) and was washed with ether (3×50 ml). The two phaseswere separated and the aqueous layer was acidified with 1 M aqueous HCluntil pH 2. The precipitated solid was then extracted with CH₂ Cl₂(3×100 ml) and the combined organic extracts were washed with waterfollowed by brine and dried over MgSO₄. Concentration in vacuum yieldeda white solid which was further purified by trituration using CH₂ Cl₂-hexane solvent system to afford N-FMOC-(R)-diphenylalanine as a whitepowder (10.7 g) in 72% yield. mp: 103-105° C., α!_(D) ²⁵ -15.4 (C=1.6,CH₂ Cl₂)

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A diarylaminopropanediol compound represented bythe formula: ##STR13## wherein Ar is a substituted or unsubstitutedaromatic group; P¹ is hydrogen or --C(O)R¹, where R¹ is a substituted orunsubstituted C₁ -C₁₀ alkyl group, a substituted or unsubstituted C₃ -C₇cycloalkyl group, a substituted or unsubstituted arylalkyl group, or asubstituted or unsubstituted phenyl group; andP² is hydrogen or--C(O)R², or --C(O)OR³, wherein R² is hydrogen, a substituted orunsubstituted C₁ -C₁₀ alkyl group, a substituted or unsubstituted C₃ -C₇cycloalkyl group, a substituted or unsubstituted arylalkyl group, or asubstituted or unsubstituted phenyl group, R³ is a substituted orunsubstituted C₁ -C₁₀ alkyl group, a substituted or unsubstituted C₃ -C₇cycloalkyl group, a substituted or unsubstituted arylalkyl group, asubstituted or unsubstituted phenyl group, a substituted orunsubstituted fluorenyl group, a substituted or unsubstituted allylgroup.
 2. The diarylaminopropanediol compound of claim 1 wherein Ar isphenyl, methylphenyl, fluorophenyl or methoxyphenyl; P¹ is hydrogen or--C(O)R¹, where R¹ is hydrogen, methyl or ethyl; and P² is --C(O)R¹,where R¹ is methyl or ethyl, or --C(O)OR³, where R³ is methyl, ethyl,t-butyl, benzyl, or 9-fluorenyl.
 3. The diarylaminopropanediol compoundof claim 1 which is a 2-(S)-diarylaminopropanediol compound having anoptical purity of at least about 70%.
 4. The diarylaminopropanediolcompound of claim 1 wherein Ar is selected from the group consisting ofa substituted or unsubstituted phenyl group and a substituted orunsubstituted naphthyl group.
 5. The diarylaminopropanediol compound ofclaim 2 wherein Ar is a phenyl group which includes at least onesubstituent selected from the group consisting of fluorine, chlorine,alkyl groups having from 1 to 10 carbon atoms, alkoxy groups having from1 to 10 carbon atoms, alkoxyalkyl groups having from 1 to 10 carbonatoms and one or more oxygen atoms, amido groups having from 1 to 10carbon atoms, fluorinated alkyl groups having from 1 to 10 carbon atomsand fluorinated alkyl groups having from 1 to 10 carbon atoms.
 6. Thediarylaminopropanediol compound of claim 5 wherein the phenyl groupincludes at least one substituent selected from the group consisting offluorine, chlorine, methyl, methoxy and trifluoromethyl.
 7. Thediarylaminopropanediol compound of claim 1 which is a2-(R)-diarylaminopropanediol compound having an optical purity of atleast about 70%.
 8. A diarylmethyloxazolidinone compound represented bythe formula: ##STR14## .
 9. The diarylmethyloxazolidinone compound ofclaim 8 having an optical purity of at least about 70%.
 10. Thediarylmethyloxazolidinone compound of claim 8 wherein Ar is selectedfrom the group consisting of phenyl, methylphenyl, fluorophenyl andmethoxyphenyl.
 11. The diarylmethyloxazolidinone compound of claim 8wherein Ar is a phenyl group which includes at least one substituentselected from the group consisting of fluorine, chlorine, alkyl groupshaving from 1 to 10 carbon atoms, alkoxy groups having from 1 to 10carbon atoms, alkoxyalkyl groups having from 1 to 10 carbon atoms andone or more oxygen atoms, amido groups having from 1 to 10 carbon atomsfluorinated alkyl groups having from 1 to 10 carbon atoms andfluorinated alkoxy groups having from 1 to 10 carbon atoms.
 12. Thediarylmethyloxazolidinone compound of claim 8 which is an(R)-diarylmethyloxazolidinone compound having an optical purity of atleast about 70%.
 13. The diarylmethyloxazolidinone compound of claim 8which is an (S)-diarylmethyloxazolidinone compound having an opticalpurity of at least about 70%.
 14. The diarylmethyloxazolidinone compoundof claim 8 wherein the phenyl group includes at least one substituentselected from the group consisting of fluorine, chlorine, methyl,methoxy and trifluoromethyl.
 15. The diarylmethyloxazolidinone compoundof claim 8 wherein Ar is selected from thc group consisting of asubstituted or unsubstituted phenyl group and a substituted orunsubstituted naphthyl group.
 16. The diarylmethyloxazolidinone compoundof claim 8 wherein Ar is phenyl, methylphenyl, fluorophenyl ormethoxyphenyl; and said diarylmethyloxazolidinone compound has anoptical purity of at least about 70%.
 17. The diarylaminopropanediolcompound of claim 1 wherein Ar is a phenyl group which includes at leastone substituent selected from the group consisting of fluorine,chlorine, alkyl groups having from 1 to 10 carbon atoms, alkoxy groupshaving from 1 to 10 carbon atoms, alkoxyalkyl groups having from 1 to 10carbon atoms and one or more oxygen atoms, amido groups having from 1 to10 carbon atoms, fluorinated alkyl groups having from 1 to 10 carbonatoms and fluorinated alkoxy groups having from 1 to 10 carbon atoms.18. The diarylaminopropanediol compound of claim 1 wherein P¹ ishydrogen or --C(O)R¹, where R¹ is an unsubstituted C₁ -C₆ alkyl group,an unsubstituted benzyl group, or an unsubstituted phenyl group.
 19. Thediarylaminopropanediol compound of claim 1 wherein P² is --C(O)R², andR² is an unsubstituted C₁ -C₆ alkyl group, an unsubstituted benzylgroup, or an unsubstituted phenyl group.
 20. The diarylaminopropanediolcompound of claim 1 wherein P² is --C(O)OR³, and R³ is an unsubstitutedC₁ -C₆ alkyl group, or an unsubstituted benzyl group.